Inheritance of OCT4 predetermines fate choice in human embryonic stem cells

Clonal cells can make different fate decisions, but it is often unclear to what extent these decisions are autonomous or predetermined. Here, we introduce a live-cell reporter for the pluripotency factor OCT4 into human embryonic stem cells to understand how they choose between self-renewal and differentiation. By tracing the histories of individual cells over multiple generations, we found that cells whose offspring were destined to differentiate showed decreased expression of OCT4 long before exposure to the differentiation stimulus. OCT4 levels were lineage-dependent; however, during cell division, mother cells distributed OCT4 asymmetrically to daughters. The resulting ratio of OCT4 between sister cells—established within minutes of mitosis—was predictive of downstream fates: cells receiving a greater ratio of maternal OCT4 showed sustained OCT4 levels and a reduced capacity to differentiate. Our observations imply that the choice between two developmental fates is almost entirely predetermined at the time of cell birth through inheritance of a pluripotency factor.